Overall treatment strategy for patients with metastatic NSCLC with activating EGFR mutations

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed

Treatment decision for recurrences in non-small cell lung cancer during or after adjuvant osimertinib: an international Delphi consensus report

IntroductionOsimertinib is recommended by major guidelines for use in the adjuvant setting in patients with EGFR mutation-positive NSCLC following the significant improvement in disease-free survival observed in the Phase III ADAURA trials. Due to limited real-world data in the adjuvant setting, little guidance exists on how to approach potential recurrences either during or after the completion of the treatment. This study aimed to reach a broad consensus on key treatment decision criteria in the events of recurrence.MethodsTo reach a broad consensus, a modified Delphi panel study was conducted consisting of two rounds of surveys, followed by two consensus meetings and a final offline review of key statements. An international panel of experts in the field of NSCLC (n=12) was used to provide clinical insights regarding patient management at various stages of NSCLC disease including patient monitoring, diagnostics, and treatment approach for specific recurrence scenarios. This study tested recurrences occurring 1) within or outside the central nervous system (CNS), 2) during or after the adjuvant-osimertinib regimen in NSCLC disease which is 3) amenable or not amenable to local consolidative therapy.ResultsPanellists agreed on various aspects of patient monitoring and diagnostics including the use of standard techniques (e.g., CT, MRI) and tumour biomarker assessment using tissue and liquid biopsies. Consensus was reached on 6 statements describing treatment considerations for the specific NSCLC recurrence scenarios. Panellists agreed on the value of osimertinib as a monotherapy or as part of the overall treatment strategy within the probed recurrence scenarios and acknowledged that more clinical evidence is required before precise recommendations for specific patient populations can be made.DiscussionThis study provides a qualitative expert opinion framework for clinicians to consider within their treatment decision-making when faced with recurrence during or after adjuvant-osimertinib treatment

Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: insights-IPF registry

Background: The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline. Methods: Six hundred twenty-three IPF patients with available QoL data (St George's Respiratory Questionnaire SGRQ, UCSD Shortness-of-Breath Questionnaire SoB, EuroQol visual analogue scale and index EQ-5D, Well-being Index WHO-5) were analysed. Mean age was 69.6 +/- 8.7 years, 77% were males, mean disease duration 2.0 +/- 3.3 years, FVC pred was 67.5 +/- 17.8%, DLCO pred 35.6 +/- 17%. Results: Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms (NYHA;p < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity (as measured by GAP score, CPI, FVC and 6-min walk test;p < 0.05 each). Multivariate analyses showed a significant association between QoL (by SGRQ total) and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment. Conclusions: Overall, IPF patients under real-life conditions have lower QoL compared to those in clinical studies. There is a meaningful relationship between QoL and various patient characteristics

Hyponatraemia-SIADH in lung cancer diagnostic and treatment algorithms

Lung cancer, in particular small cell lung cancer (SCLC), is a very aggressive solid tumour with limited therapeutic options to date. The majority of patients present, at the time of diagnosis, with extensive disease patterns and reduced performance status. Hyponatraemia is a common finding in SCLC (25%) which can be assigned to a paraneoplastic syndrome termed syndrome of inappropriate ADH secretion (SIADH) in 60% of cases. Hyponatraemia may cause significant and even dramatic neurocognitive deficits, if not treated in an effective manner. Palliative chemo- or radiotherapy is restricted to patients with good performance status and therapeutic adherence. Acute or persistent hyponatraemia may interfere with such treatment options and compromise outcome. This review integrates new diagnostic and therapeutic guidelines to improve the understanding how and when to treat hyponatrearnia in thoracic oncology patients Integrating early palliative care in lung cancer patients has a significant impact on prognosis. Correcting hyponatraemia in a supportive and risk stratified fashion may help to improve both prognosis and quality of life and should be a standard in modern palliative care for patients with lung cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved

Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma

Aim: To assess outcomes in patients with advanced adenocarcinoma non-small-cell lung cancer who received nintedanib plus docetaxel after progression on prior chemotherapy followed by immune checkpoint inhibitor (ICI) therapy. Patients & methods: VARGADO is a prospective, noninterventional study. We describe initial data from a cohort of 22 patients who received nintedanib plus docetaxel after chemotherapy and ICI therapy. Results: Median progression-free survival with nintedanib plus docetaxel was 5.5 months (95% CI: 1.9–8.7 months). The objective response rate was 7/12 (58%) and the disease control rate was 10/12 (83%). Data for overall survival rate 12 months after the start of treatment (primary end point) are not yet mature and are not reported. Of 22 patients, 73% experienced drug-related adverse events; adverse events led to treatment discontinuation in 32% of patients. Conclusion: These data highlight the potential clinical benefit of nintedanib plus docetaxel in patients who failed prior ICI therapy. Trial registration number: NCT0239245

Euvolemic hyponatremia in cancer patients. Report of the Hyponatremia Registry: an observational multicenter international study

Hyponatremia secondary to SIADH is frequent in cancer patients and potentially deleterious. The aim of this sub-analysis of the Hyponatremia Registry database is to analyze current diagnostic and therapeutic management practices in cancer patients with SIADH. We analyzed 358 cancer patients who had serum sodium concentration ([Na+]) = 130 mEq/L. Overly rapid correction of hyponatremia occurred in 11.7%. Although essential for successful hyponatremia management, appropriate diagnostic testing is not routinely performed in current practice. The most frequently employed monotherapies were often ineffective and sometimes even aggravated hyponatremia. Tolvaptan was used less often but showed significantly greater effectiveness. Despite clear evidence that hyponatremia is associated with poor outcome in oncology patients, most patients were discharged still hyponatremic. Further studies are needed to assess the beneficial impact of hyponatremia correction with effective therapies

A stop codon polymorphism of toll-like receptor 5 is associated with a stable course of chronic obstructive lung disease

The etiology of chronic obstructive lung disease (COPD) is unclear. It is supposed to be the product of an exogenous antigenic stimulus, such as tobacco smoke, and an endogenous genetic susceptibility. Toll-like receptors (TLR) are signal molecules, essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS) binds to TLR4 and two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have recently been described. TLR5 is the receptor for flagellin, aconstituent of Gram-positive and -negative bacterial flagella. A functional relevant TLR5 polymorphism (TLR5392STOP) has already been identified. The coactivation of both TLR4 and 5 seems to play an important role in the mediation of host-defense mechanisms. We genotyped 138 Caucasian patients with COPD and 135 healthy controls for the TLR5 polymorphism TLR5392STOP respectively for Asp299Gly and Thr399Ile polymorphisms in theTLR4gene. Among COPD patients the prevalence for the TLR5 mutant allele was 9.42% (26/276). The prevalence for each Asp299Gly and Thr399Ile mutant allele was 4.71% (13/276). In the control group the TLR5 mutation prevalence was 5.19% (14/270) (P = 0.138), the prevalence of each TLR4 polymorphism was 2.96% (8/270) (p = 0.279). In the subgroup of 54 patients with a stable course of COPD, defined as less than three hospitalizations over the last three years due to COPD, we found a significant association with the TLR5392STOP gene polymorphism (P = 0.026). These data suggest that the TLR5392STOP polymorphism is associated with a stable course of COPD, whereas TLR4 polymorphisms have no impact neither on the onset nor on the course of COPD

Classification of properties and their relation to chemical bonding: Essential steps toward the inverse design of functional materials

To design advanced functional materials, different concepts are currently pursued, including machine learning and high-throughput calculations. Here, a different approach is presented, which uses the innate structure of the multidimensional property space. Clustering algorithms confirm the intricate structure of property space and relate the different property classes to different chemical bonding mechanisms. For the inorganic compounds studied here, four different property classes are identified and related to ionic, metallic, covalent, and recently identified metavalent bonding. These different bonding mechanisms can be quantified by two quantum chemical bonding descriptors, the number of electrons transferred and the number of electrons shared between adjacent atoms. Hence, we can link these bonding descriptors to the corresponding property portfolio, turning bonding descriptors into property predictors. The close relationship between material properties and quantum chemical bonding descriptors can be used for an inverse material design, identifying particularly promising materials based on a set of target functionalities